IE47903B1

IE47903B1 - Polysubstituted-2-(3-loweralkylamino-2-r o-propoxy) pyridines,process for preparing the same,and pharmaceutical compositions containing the same

Info

Publication number: IE47903B1
Application number: IE13/79A
Authority: IE
Original assignee: Merck & Co Inc
Priority date: 1978-01-04
Filing date: 1979-01-03
Publication date: 1984-07-25
Also published as: EP0003278A1; JPS54106476A; IE790013L; IT7947514A0; DK2379A; IT1188812B

Abstract

Novel substituted (3-loweralkylamino-2-R1O-propoxy) pyridines, their pharmaceutically acceptable salts and formula wherein n is 3, 4, 5 or 6, R is C3-C4 branched alkyl, R1 is H or -@-L wherein L is selected from C1-C10 alkyl, phenyl and substituted phenyl having up to two substituents which are independently selected from C1-C4 alkyl, C1-C4 alkoxy and halo, R2 is F, CN, CF3, Cl, , NO2, -COOR5 wherein R5 is H, C1-C6 alkyl or C6-C12 carbocyclic aryl, -CONR6R7 wherein R6 and R7 when separate, are H or C1-C6 alkyl and when joined, are -CH2-(CH2)3-CH2-, -CH2-CH2-O-CH2-CH2, -CH2-CH2-NH-CH2-CH2- or -CH2- CH2-N(CH3)-CH2-CH2-, and R3 and R4 are independently selected from H, C1-C4 alkyl, CF3, F, C1-C4alkyl-@-NH, phenyl and substituted phenyl wherein said substituents are independently selected from C1- C4alkyl, C1-C4alkoxy and halo, such that one of R3 and R4 is other than H, and pharmaceutically acceptable salts thereof, and their preparation are disclosed. These pyridines have pharmaceutically useful properties such as beta -adrenergic blocking activity.

Description

The present invention concerns substituted (3loweralkylamino-2-R^O-propoxy)pyridines having pharmaceutically useful properties. β-Adrenergic blocking agents or β-blockers 5 are known to be useful in treating certain cardiovascular disorders such as arrhythmia and angina pectoris. While these β-blockers can also have antihypertensive activity, the onset of this activity is generally gradual. The structure and activity of β-blockers is generally discussed lu in Clinical Pharmacology and Therapeutics 10, 252, 306 (1969). Substituted N-heteroaryl β-adrenergic blocking agents are disclosed in British patent 1,305,644, U.S. 4,000,282, U.S. 3,946,009, Journal of Medicinal Chemistry 16, 1113-1114 (1973) and Journal of Medicinal Chemistry , 1321 (1972).

Substituted (3-loweralkylamino-2-R^Opropoxy)pyridines have been discovered. These compounds have β-adrenergic blocking activity; some compounds also have antihypertensive activity of immediate onset.

The present invention provides a compound having the formula wherein n is 3, 4, 5 or 6, R is or C4 branched alkyl, R^ is H or -C-L wherein L is selected from Cl-C10 alky·1·' phenyl and substituted phenyl having up to two substituents which are independently selected from C^-C^ alkyl, C^-C^ alkoxy and halo, is F, CN, CF3, Cl, no2, -COORg wherein Rg is H, C^-Cgalkyl or Cg-C^j carbocyclic aryl, -CONRgR? wherein Rg and R? when separate, are H or C^-Cgalkyl and when joined, are -ch2-(ch2)3-ch2, -ch2-ch2-o-ch2-ch2-, -CH2-CH2-NH-CH2-CH2-, or -CH2-CH2-N{CH 3)-CH2-ch2-, or a pharmaceutically acceptable salt thereof.

R1 is H or the -C-L group, with H being preferred. The L group includes C^-C^q, linear and branched hydrocarbon alkyl such as methyl, n-decyl, tert butyl, isoamyl and n-heptyl,with C1~C4 alkyl being preferred, and phenyl or mono- and disubstituted phenyl such 7 9 0 3 as tert butylphenyl, 2,6-dibromophenyl, 3-methylphenyl, 4-n-propylphenyl, 3,5-dimethoxyphenyl, 4-iodophenyl, 2-methyl-4-chlorophenyl and 4-fluorophenyl, with monosubstituted phenyl preferred.

The R2 ester groups are C^-C^alkyIester exemplified by -COOCH3, -COOCgH13, -COOCH (CH3)2 and -COOC2H5 and Cg-C12 carbocyclic aryl ester exemplified by CgHg-OOC, p-CI^-CgH^OOC-, CgHg-CgH^-OOC- and Ο^θΗγ-ΟΟΟ-; and the amide groups include -CONH_, Cn-C, substituted amide groups such as z J_ u -CON(CH3)2, -CON(CgH13)2, -CONHC2H5 and -CON (sec butyl)., and carbonyl heterocyclic groups such as θ /-λ » f~\ ° r\ -C-N S > , -C-N S NH and -C-N S 0. \__/ \__y \_y R is isopropyl, sec butyl, or tert butyl with tert butyl being preferred.

The alkylene moiety bridging positions 4-5 in Formula I may have from 3-6 units. The -CH2-CH2-CH2- and -CH2~(CH2)2-CH2-groups are preferred.

Examples of compounds of Formula I are O-C-(CHg)g-CHg iii-CHg -NH-isopropy 1 More preferred compounds of Formula X are those wherein n is 3 or 4, more preferably when R2 is CN or F, and most preferably when R2 is CN, Rg is H and R is tert butyl.

The substituted pyridines of the present invention include all the optical isomer forms, that is mixtures of enantiomers e.g. racemates as well as the individual enantiomers. These individual enantiomers are commonly designated according to the optical rotation they effect, by (+) and (-), (L) and (D), (1) and (d) or combinations of these symbols. The symbols (S) and (R) stand for sinister and rectus respectively and designate an absolute spatial configuration of the θ enantiomer. The (S) isomer is a preferred isomer configuration.

The pyridines of the present invention can be prepared by any convenient process.

One such process involves the coupling of a 5 halopyridine with a suitable substituted oxazolidine and hydrolyzing the reaction product obtained. This process is illustrated by the following Set Of reaction equations: Reaction A R. '2 + MO-CH.

N halo O-CH. 0. NR VI VII 7 9 0 3 NR X Η Υ Halo may be Cl, Br and I, with Cl being preferred. M is an alkali metal, either potassium or sodium. Y can be hydrogen or the residue of any suitable aldehyde Y-C Ή e.g. an arylaldehyde, such as benzaldehyde or naphthaldehyde or an alkanal such as acetaldehyde or butyraldehyde. The process for preparing oxazolidines where M is hydrogen is disclosed in U.S. 3,718,647 and U.S. 3,657,237 and to the extent necessary the 10 pertinent disclosure is incorporated herein by reference.

The alkali metal salt of the oxazolidine is prepared in a conventional manner by reaction of the corresponding hydroxymethyloxazolidine with an appropriate amount of an alkali base reactant. However, this Reaction A may also be carried out with in-situ formation of the alkali metal oxazolidine salt (Formula VI) by reacting the oxazolidine VIII with the Formula V pyridine in the presence of a strong base such as an alkali metal alkoxide (e.g. K-O-C-(CH^) or sodium hydride.

The coupling reaction can be carried out at temperatures ranging from about 0°C to the reflux temperature of the solvent. A temperature range of 1O°C to 75°C is preferred. The reaction is generally carried out in a solvent. Any suitable solvent may be used. Examples of useful solvents are dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, tert.butanol and alkanols.

The hydrolysis is carried out using conventional acid hydrolysis reagent and techniques e.g. treatment with a solution of an acid such as acetic acid or any strong mineral acid such as HCl or ^SO^. The hydrolysis product can be directly obtained as the salt of the acid used for the hydrolysis. Ordinarily, the product I is recovered as the free base after conventional neutralization of the salt.

The coupling reaction is ordinarily carried out at atmospheric pressure. Higher pressures may be used if desired.

When a racemic oxazolidine (Formula VI or VIII) is used as a reactant, the product is obtained as a racemate. The racemate may be separated into its individual enantiomers by conventional resolution techniques.

When Y in the oxazolidine e.g. (Formula VI or VIII) is other than hydrogen, in addition to the chiral center at oxazolidine position 5 there is a second chiral center at position 2. However, whenever the oxazolidine is designated e.g. as (S), (R) or (R,S), this designation refers only to the optical configuration around the carbon atom at the 5 position.

By using a single optical isomer of said oxazolidine in the above reactions, the product may be obtained directly as a single enantiomer. Thus, if the S-isomer of the oxazolidine is used, then the product obtained will be the S-isomer. This provides a convenient way for directly preparing individual isomers of the present pyridines.

The intermediates of Formula V may be prepared by any conventional process. Especially useful processes involve the condensation of alkylidenemalononitriles or alkylidinecyanoacetates with either HC(OC2Hg)3 or X(°CH ) dimethylformamide dimethylacetal (H-C and ^(οη3)2 cyclizing the unsaturated intermediate product with acid to provide Formula V compounds. These especially useful processes are an extension of the processes described by Bryson et al in J, Org. Chem. 41 2066 (1976) and J. Org. Chem. 39, 3436 (1974). The aforesaid malononitriles and cyanoacetates are prepared by methods available in the literature.

The following reaction equations illustrate the condensation reactions: METHOD A CN(or COOC2H5 OCH, / \ + CN / DMF, H-C—OCH, N(CH3)2 DMF acetal METHOD B C-N(CH3)2 λ I c=c J \ ,CN (or CN(or COOC2H5) J\ O-C2H5 + H-C—'OC2H5 O-CH2H5 8η012/Αθ2θ 7 3 U 3 z\ (or COOC2H5 HBr CHjCOOH The intermediate pyridines of Formula V having a CF3 substituent are obtained by hydrolyzing the ester group to the acid (COOH) and treating this derivative with a fluorinating agent e.g. SF4/HF to obtain the CF3 group.

Pyridines of the present invention wherein is other than hydrogen are conveniently prepared by treating the corresponding pyridine where R^ is hydrogen with an appropriate acylating agent such as an acyl halide, e.g. undecanoyl chloride, pivaloyl chloride, benzoylchloride, p-methoxybenzoyl chloride, an anhydride e.g. acetic anhydride. The reaction is illustrated by the following equations: (L-ί )2O The compounds of the present invention also include the pharmaceutically acceptable salts of the novel pyridines. These salts are generally salts of the Formula I pyridines and organic or inorganic acids.

These salts are prepared by treating the pyridine with an appropriate amount of a useful acid, generally in a suitable solvent. Examples of useful organic acids are isethionic acid and carboxylic acids such as maleic acid, acetic acid, tartaric acid, propionic acid, fumaric acid, succinic acid, 10 pamoic acid, oxalic acid and pivalic acid; useful inorganic acids are hydrohalo acids such as HCl, HBr, HI; sulfuric acid and phosphoric acid.

The hydrochloride and hydrogen maleate salts are examples of preferred salts.

T·5 The compounds of the present invention have β-adrenergic blocking activity. This activity is useful in treating cardiovascular related disorders such as angina pectoris, arrhythmia and tachychardia. This β-adrenergic blocking activity may also be manifested in an antihyper2° tensive effect of gradual onset after extended administration of the pyridine compound.

The β-adrenergic blocking activity of the present pyridine is determined by measuring the ability of representative pyridines to block the β-adrenergic stimulant effect of isoproterenol.

Some of the present pyridines also exhibit antihypertensive activity of immediate onset This antihypertensive activity is believed to be the result of peripheral vasodilation via a mechanism not directly re}0 lated to β-adrenergic blockade.

This rapid onset antihypertensive activity is determined by administering a representative 4-79 0 3 pyridine of the present invention to spontaneously hypertensive (SH) rats and measuring the effect on blood pressure.

The observed β-adrenergic blocking activity of the present pyridines in test animals indicates that they are useful in humans as Sadrenergic blocking agents.

The ability of certain of the present pyridines to reduce blood pressure, in an SH rat, rapidly and for extended duration, also indicates that the present pyridines are useful to treat hypertension in humans.

For use as S-adrenergic blocking agents, and/or antihypertensive agents the compounds of the present invention can be administered orally, by inhalation, by suppository or parenterally i.e. intravenously, intraperitoneally, etc. and in any suitable dosage form. The compounds may be offered in a form (1) for oral administration e.g. as tablets in combination with other compounding ingredients (diluents or carriers) customarily used such as talc, vegetable oils, polyols, benzyl alcohols, starches and gelatin - or dissolved, dispersed or emulsified in a suitable liquid carrier - or in capsules or encapsulated in a suitable encapsulating material; or (2) for parenteral administration, dissolved, dispersed, or emulsified in a suitable liquid carrier or diluent or (3) as an aerosol or (4) as a suppository. The ratio of active ingredient (present pyridine) to compounding ingredients will vary as the dosage form requires. Conventional procedures are used to prepare the pharmaceutical formulations.

The dosage level for the present compounds may be varied from 0.01 mg. to 50 mg. per kilogram of animal body weight per day. Daily doses ranging from 0.04 to 2,5 mg/kg are preferred, with 0.08 to 1.25 mg/kg being a more preferred range. Oral administration is preferred. Either single or multiple daily doses may be administered depending on unit dosage.

Thus, another embodiment of this invention is a pharmaceutical composition containing β-adrenergic blocking or antihypertensive amount of a compound of the present invention.

The following examples illustrate the Method A and B preparations and conversion of the ester to the CFg derivative. Temperatures are in 0 Celsius. Examples 1 and 2 have been retained to illustrate the Method A and B preparations although these Examples no longer cover compounds within the scope of the invention. Furthermore, Example 2 illustrates the preparation of the compounds of Example Nos 3 and 4 of Table 1. Similarly Examples 5 and 6 have been retained so as to illustrate the preparation of the compounds of Example Nos. 7 and 8 of Table 2. ·’ 4 7 9 Ο 3 EXAMPLE 1 METHOD A - Preparation of 2-Bromo-3-trifluoromethyl5-methylpyridine a. To a solution of ethylpropylidene cyanoacetate (11.4 g, 0.074 m) in absolute ethanol (75 ml) was added DMF acetal (8.9 g, 0.074 m). After the addition, the solution was heated at reflux for 6 hours and then concentrated to dryness to yield 16.0 grams of crude 2-cyano-5- (Ν,N-dimethylamino) -4-methyl-2,4-pentanedienoate. b. The crude 2-oyano-5-(N,N-dimethylamino)-4-methyl2,4-pentanedienoate (15.9 g) was dissolved in acetic acid (50 ml) and the mixture heated at 40°. A solution of 30% HBr/acetic acid (100 ml) was added dropwise and then the mixture was heated to 55° with stirring. After heating for 3/4 of an hour, the solution was poured onto ice, neutralized with solid Na2CO3 and extracted with CH2C12 (4X200 ml). The organic extracts were dried over Na2SO4, filtered and concentrated to dryness. The residue was distilled at 114-120® (0.4 mm) to yield 6.3 g (35% yield) of ethyl 2-bromo-5-methylnicotinate c. A mixture of ethyl 2-bromo-5-methylnicotinate (7.1 g, 0.03 m) and 10% NaOH solution (500 ml) was heated on a steam bath with stirring. After 3 hours, the solution was cooled and neutralized with 12N HCl. After cooling in an ice bath, the mixture was filtered to yield 5.6 g (39% yield) of 2-bromo-5-methylnicotinic acid.

The 2-bromo-5-methylnicotinic acid (5.0 g, 0.023m), SF^ (31 g; 0.020 m) and HF (5.3 ml) were charged to a steel bomb. The contents were heated at 120® for 8 hours.

After cooling to room temperature, the bomb was opened and the contents poured into saturated Na2CO3 solution and extracted with CHClj (3X100 ml) . The organic layer was dried over Na2SO4, filtered and concentrated to dryness. The residue distilled at 45-49° (0.1 mm) to yield 4 g (59% yield) of 2-bromo-3-trifluoromethyl-55 me thylpyridine.

EXAMPLE 2 METHOD B - Preparation of 2-Bromo-3-cyano-5-methylpyridine a. A mixture of 1-propylidenemalononitrile (11.3 g, 0.104 m), acetic anhydride (21 ml), HC(OEt)3 (16.3 g, 0.11 m) and ZnCl2 (100 mg) was heated overnight at 145°.

After 18 hours, the volatiles were removed by distillation at atmospheric pressure, acetic anhydride (5 ml) and HC(OC2H5)3 (4 ml.) were added and the mixture heated at 150°. After 10 hours, the solution was cooled and added to saturated Na2CO3 solution. The aqueous solution was extracted with CHC13 (3X100 ml). The organic layer was dried over Na2SO4, filtered and concentrated to dryness.

The residue distilled at 138-158° (0.3 mm) to give 11.2 g (67% yield) of l,l-dicyano-4-ethoxy-3-methyl-l,3-butadiene. b. l,l-Dicyano-4-ethoxy-3-methyl-l,3-butadiene (11.2 g) was cyclized using basically the same procedure as Example 1 b.; and 3.0 g (15% yield) of 2-bromo-3-cyano-5methylpyridine, m.p. = 109°-lll°, were obtained.

The following table lists the Formula V inter25 mediates which were prepared using the processes substantially as disclosed in Examples 1 and/or 2, as applicable.

TABLE FQ +, H CF ϋ OS 3 2 Ό · 6 0 cu s Μ · — CM S +J dP □ rQ 3 Η I Ό 0) Ο ·Η +J Μ ί» CF & £ υ o m d <*> I—ί I o in oo CM dP m r4 I CF O υ o in o r—i I co o (“i ϋΡ tn i-i I CF «a· ««a* EXAMPLE 5 (S) 4-Methy1-2-(3-tert butylamino-2-hydroxypropoxy)-3trifluoromethylpyridine hydrogen maleate A dry flask was charged, under nitrogen, with (S) 2-phenyl-3-tert butyl-5-hydroxymethyloxazolidine (7.0 g, 0.03 m), dimethylformamide (DMP) (80 ml) and NaH (50% mineral oil, 1.3 g, 0.027 m) and heated, with stirring, at 90° for 30 minutes. After cooling to room temperature, 2-bromo-4-methyl-3-trifluoromethylpyridine (6.2 g, 0.026 m) in DMF (25 ml) was added and the mixture was stirred at 45°. After stirring overnight at 45°, the mixture was poured into saturated Na2CO3 (300 ml) and water (300 ml) and extracted with Et2O (4X300 ml). The organic layer was washed with water (2X300 ml) and cold IN HCl (3X200 ml). The acid layer was poured into sodium acetate . 3H2O (82 g, 0.6 m) and the solution stirred at room temperature. After six hours, the solution was extracted with EtjO (2X250 ml). The aqueous layer was neutralized with saturated Na2COj and extracted with CH2C12 (4X200 ml). The organic layer was dried over Na2SO^, filtered and concentrated to dryness. The residue was chromatographed on silica gel 60 and the product eluted with 20% CH^OHCHC13· The crude product was crystallized with maleic acid in isopropanol to give 0.8 g (8% yield) of (S) 4-methyl2-(3-tert butylamino-2-hydroxypropoxy)-3-trifluoromethylpyridine hydrogen maleate, m.p. = 126e-128° (EtjO-isopropanol).

EXAMPLE 6 (S) 3-Cyano-4,5-dimethyl-2-(3-tert butylamino-2-hydroxypropoxy)pyridine hydrogen maleate A dry flask was charged, under nitrogen, with tert butanol (50 ml), potassium metal (0.58 g, 0.015 m), and (S) 2-phenyl-3-tert butyl-3-hydroxymethyloxazolidine (4 g, 0.017 m) and heated at 40° with stirring until all the potassium metal reacted. Then, 2-bromo-3-cyano-4,5dimethylpyridine (3.0 g, 0.014 m) in tert butanol (5 ml) was added and the mixture heated at 70°. After heating overnight, the mixture was concentrated to dryness and stirred with water (150 ml) and acetic acid (9.0 g). After five hours, the solution was extracted with Et2O (2X100 ml).

The aqueous layer was neutralized with saturated Na2CO3 and extracted with CHC13 (3X100 ml). The organic layer was dried over Na2SO4, filtered and concentrated to dryness. The residue was crystallized with maleic acid in isopropanol to give 4.1 g (75% yield) of (S) 3-cyano4,5-dimethyl-2-(3-tert butylamino-2-hydroxypropoxy)pyridine hydrogen maleate, m.p. » 148o-150° (Et2O-isopropanol). 479 03 The free base may be obtained from the hydrogen maleate salt by conventional neutralization with an appropriate base. Other salts may be prepared from the free base by treating with an appropriate acid.

The following Table contains additional examples of the Formula I pyridines which were prepared using the appropriate Formula V intermediates in a procedure substantially as described in Examples 5 or 6.

TABLE 2 7903 While the Examples are directed to (S) isomers, the corresponding (R) isomer or (R/S) racemate is prepared by substituting the appropriate (R) or (R/S) oxazolidine for the (S) oxazolidine in the processes illustrated by Examples 5-8.

Claims

1. CLAIMS:1. A compound having the formula wherein n is 3, 4, 5 or 6, R is C 3 or branched alkyl, is H or -§-L wherein L is selected from C^-C^ Q alkyl, phenyl and substituted phenyl having up to two substituents which are independently selected from C^-C^ alkyl, C^-C^ alkoxy and halo, R 2 is F, CN, CF 3 , Cl, -N< , N0 2 , -COORjj wherein Rg is H, C^-Cg alkyl or Cg-C^ 2 carbocyclic aryl, 15 -CONRgR? wherein R g and R ? when separate, are H or C^-Cg alkyl and when joined, are -CH 2 -(CH 2 ) 3 -CH 2 -, -CH 2 -CH 2 -O-CH 2 -CH 2 -, -CH 2 -CH 2 -NH-CH 2 -CH 2 - or -CH 2 -CH 2 -N(CH 3 )-CH 2 -CH 2 -, 20 or a pharmaceutically acceptable salt thereof.

2. A compound of Claim 1 having the S-isomer configuration.

3. A compound of Claim 1 wherein n is 3 or 4, R 2 is H and R is tert butyl. 479 0 3

4. a pharmaceutical composition for effecting β-adrenergic blocxade containing an effective amount of a compound of Claim 1 in association with a pharmaceutically acceptable excipient tnerefor.

5. 5. A process for preparinc a compound having the formula wherein n, R and R 2 comprises hydrolyzing a are as defined in Claim 1, which compound of the formula wherein n and Y is , R and R 2 , have the meanings indicated above an aldehyde residue. compound A process according to Claim 5 wherein said has the (S) isomer configuration.